Related Experiment Video
Updated: Mar 15, 2026
09:37
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
10.6K
Genetic Background Limits Generalizability of Genotype-Phenotype Relationships
Laura J Sittig1, Peter Carbonetto2, Kyle A Engel2
1Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA; Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Neuron
|September 13, 2016
Summary
Genetic background significantly impacts psychiatric disease gene research in mice. Findings in one mouse strain may not apply to others, challenging current research assumptions and reproducibility.
Area of Science:
- Neuroscience
- Genetics
- Psychiatric Research
Background:
- Genome-wide association studies (GWASs) identify genetic loci for psychiatric diseases.
- Genetically engineered mouse models are crucial for characterizing these disease-associated genes.
- Current research assumes genotype-phenotype relationships in mice generalize across different genetic backgrounds.
Purpose of the Study:
- To directly test the assumption that genotype-phenotype relationships observed in one mouse genetic background are generalizable.
- To assess the impact of genetic background on the interpretation of gene function in psychiatric disease models.
Main Methods:
- Generated F1 hybrid mice by crossing C57BL/6J mice (heterozygous for Cacna1c and Tcf7l2 null alleles) with wild-type females from 30 diverse inbred mouse strains.
- Analyzed genotype-phenotype interactions across these different genetic backgrounds.
Main Results:
- Observed extremely strong genetic background interactions influencing phenotype outcomes.
- These interactions sometimes led to diametrically opposing conclusions regarding gene function.
- Demonstrated significant variability in genotype-phenotype relationships across different inbred strains.
Conclusions:
- Genotype-phenotype relationships in mouse models of psychiatric disease cannot be reliably inferred from a single genetic background.
- The significant influence of genetic background poses a major challenge to the reproducibility and generalizability of current mouse model research.
- Further research must account for genetic background effects to improve the translation of mouse findings to human psychiatric conditions.
Related Concept Videos
02:27Background and Environment Affect Phenotype
8.0K
Although the genetic makeup of an organism plays a major role in determining the phenotype, there are also several environmental factors, such as temperature, oxygen availability, presence of mutagens, that can alter an organism’s phenotype.
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...
8.0K
01:28Human Genetics
1.8K
Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...
The complex relationship between genetics and psychology is observable through common biological components such...
1.8K
01:27Principles of Pharmacogenetics: Types of Genetic Variants
72
The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
72
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
93
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
93
01:20Gene-Environment Interactions
1.5K
Gene expression is a dynamic process that is significantly influenced by environmental factors. This interaction underlies the complex nature of biological development and the phenotypic differences observed among individuals, even among those with identical genetic makeups. Factors such as radiation, temperature, behavior, nutrition, and stress play pivotal roles in determining how genes are expressed. The concept of the reaction range is central to understanding this interaction. It posits...
1.5K
01:27Pharmacogenetics of Drug Metabolism: Overview
88
Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
88